Andrzej Szczeklik

EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity.

Abstract:  Aspirin and other nonsteroidal anti‐inflammatory drugs (NSAIDs) are among the most common causes of adverse drug reactions. Majority of them are of the hypersensitivity type. The two frequent clinical presentations of aspirin hypersensitivity are: aspirin‐induced bronchial asthma/rhinosinusitis (AIA/R) and aspirin‐induced urticaria/angioedema (AIU). The decisive diagnosis is based on provocation tests with aspirin, as the in vitro test does not hold diagnostic value as yet. Detailed protocols of oral, bronchial and nasal aspirin provocation tests are presented. Indications, contraindications for the tests, the rules of drug withdrawal and equipment are reviewed. Patient supervision and interpretations of the tests are proposed.

Hypersensitivity to nonsteroidal anti‐inflammatory drugs (NSAIDs) – classification, diagnosis and management: review of the EAACI/ENDA# and GA2LEN/HANNA*

To cite this article: Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet J, Bousquet P, Celik G, Demoly P, Gomes ER, Niżankowska‐Mogilnicka E, Romano A, Sanchez‐Borges M, Sanz M, Torres MJ, De Weck A, Szczeklik A, Brockow K. Hypersensitivity to nonsteroidal anti‐inflammatory drugs (NSAIDs) – classification, diagnosis and management: Review of the EAACI/ENDA and GA2LEN/HANNA. Allergy 2011; 66: 818–829.

Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs.

Hypersensitivity reactions to aspirin (acetylsalicylic acid) and other nonsteroidal anti‐inflammatory drugs (NSAIDs) constitute only a subset of all adverse reactions to these drugs, but due to their severity pose a significant burden to patients and are a challenge to the allergist. In susceptible individuals, NSAIDs induce a wide spectrum of hypersensitivity reactions with various timing, organ manifestations, and severity, involving either immunological (allergic) or nonimmunological mechanisms. Proper classification of reactions based on clinical manifestations and suspected mechanism is a prerequisite for the implementation of rational diagnostic procedures and adequate patient management. This document, prepared by a panel of experts from the European Academy of Allergy and Clinical Immunology Task Force on NSAIDs Hypersensitivity, aims at reviewing the current knowledge in the field and proposes uniform definitions and clinically useful classification of hypersensitivity reactions to NSAIDs. The document proposes also practical algorithms for the diagnosis of specific types of NSAIDs hypersensitivity (which include drug provocations, skin testing and in vitro testing) and provides, when data are available, evidence‐based recommendations for the management of hypersensitive patients, including drug avoidance and drug desensitization.

Safety of a specific COX‐2 inhibitor in aspirin‐induced asthma

In a subset of patients with asthma, aspirin and several other non‐steroidal anti‐inflammatory drugs (NSAID) that inhibit simultaneously cyclooxygenase‐1 (COX‐1) and cyclooxygenase‐2 (COX‐2) precipitate dangerous asthmatic attacks.

Anti-inflammatory effects of simvastatin in subjects with hypercholesterolemia

AIMS Beneficial effects of statins in preventing cardiovascular events may depend, at least in part, on their anti-inflammatory action. The aim of the study was to assess the influence of simvastatin and aspirin on serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in hypercholesterolemic subjects. METHODS AND RESULTS In 33 asymptomatic men with total cholesterol (TC) >6.5 mmol l(-1) and in 25 men with coronary heart disease and borderline-high cholesterol levels (between 5.2 and 6.5 mmol l(-1)) chronically treated with low-dose aspirin (75 mg/d), serum levels of CRP, TNF-alpha, IL-6, and IL-8 were determined before and after a 3-month simvastatin therapy (20-40 mg daily). In the former group, these markers of inflammation were also measured before and after a 2-week treatment with aspirin (300 mg/d), implemented prior to and in combination with simvastatin. A distinct reduction of CRP and TNF-alpha was found in both groups; IL-6 levels were decreased only in subjects with marked hypercholesterolemia. Aspirin had no effect on the anti-inflammatory action of simvastatin. CONCLUSIONS In men with hypercholesterolemia simvastatin treatment lowers serum levels of CRP and proinflammatory cytokines. Low-dose aspirin does not add to the anti-inflammatory action of simvastatin.

Nasal provocation test with lysine-aspirin for diagnosis of aspirin-sensitive asthma

Nasal provocation tests (NPTs) with lysine-aspirin (L-ASA) have been recently introduced for assessment of aspirin-induced asthma (AIA). They differ in dose and means of aspirin instillation, duration of observation period, and criteria for positivity. Thus far they have not become a routine part of clinical diagnosis. Fifty-one patients with AIA, confirmed by oral challenge test, were recruited to undergo diagnostic NPTs with L-ASA. In 10 of these patients (19.6%), NPTs could not be performed because of total obstruction of at least one nostril or marked fluctuations in nasal flows, leaving 41 patients with AIA for the study. Control groups consisted of 13 aspirin-tolerant asthmatic patients and 10 healthy subjects. L-ASA at a total dose of 16 mg of acetylsalicylic acid applied bilaterally into the inferior nasal conchae caused significant fall in inspiratory nasal flow in at least one nostril (>40%), which was measured by anterior rhinomanometry, and clinical symptoms of watery discharge and nasal blockage in 35 of 41 patients with AIA, one of 10 healthy subjects, and none of 13 aspirin-tolerant asthmatic patients. No relationship was found between the baseline nasal flow values and the intensity of response to L-ASA. No systemic reactions, including bronchospasm, were noticed, even in patients whose initial FEV1 was lower than 70% of predicted value. This test is highly specific (95.7%) and sensitive (86.7%), but negative results do not exclude possible intolerance to aspirin (predictive value of a negative result 78.6%). In conclusion, the NPT described is a simple, safe, and quick test for diagnosis of AIA. It can be used in patients with unstable asthma. It may be a method of choice to confirm hypersensitivity to aspirin manifested only by symptoms from the upper respiratory tract. Patients suspected of aspirin intolerance who have negative NPT results should undergo bronchial or oral challenge tests with aspirin.

Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia.

OBJECTIVES To assess the effects of aspirin compared with simvastatin on thrombin generation in hypercholesterolemic men, and to establish whether the reduction of elevated blood cholesterol by simvastatin would affect the action of aspirin on thrombin formation. BACKGROUND Aspirin inhibits thrombin formation, but its performance is blunted in hypercholesterolemia. By virtue of altering lipid profile, statins could be expected to influence thrombin generation. METHODS Thirty-three men, aged 34 to 61 years, with minimal or no clinical symptoms, serum total cholesterol >6.5 mmol/liter and serum triglycerides <4.6 mmol/liter, completed the study consisting of three treatment phases. First, they received 300 mg of aspirin daily for two weeks (phase I), which was then replaced by simvastatin at the average dose of 24 mg/d for three months (phase II). In phase III, aspirin, 300 mg/day, was added for two weeks to simvastatin, the dose of which remained unchanged. Thrombin generation was assessed: 1) in vivo, by measuring levels of fibrinopeptide A (FPA) and prothrombin fragment 1+2 (F1+2) in venous blood; and 2) ex vivo, by monitoring the rates of increase of FPA and F1+2 in blood emerging from standardized skin incisions of a forearm. A mathematical model was used to describe the kinetics of thrombin formation at the site of microvascular injury. RESULTS Two-week treatment with aspirin had no effect on thrombin markers in vivo, while ex vivo it depressed the total amount of thrombin formed, though not the reaction rate. After simvastatin treatment, serum cholesterol decreased by 31% and LDL cholesterol by 42%, while thrombin generation became markedly depressed. In venous blood, FPA was significantly reduced. Concomitantly, the initial thrombin concentration and total amount of thrombin generated decreased significantly. Addition of aspirin to simvastatin (phase III) had no further effect on any of these parameters. CONCLUSIONS In men with hypercholesterolemia, lowering serum cholesterol level by a three-month simvastatin treatment is accompanied by a marked reduction of thrombin generation both at basal conditions in venous blood and after activation of hemostasis by microvascular injury. Once blood cholesterol became reduced, adding aspirin to simvastatin did not enhance dampening of thrombin formation.

Relationship between bleeding time, aspirin and the PlA1/A2 polymorphism of platelet glycoprotein IIIa

A single nucleotide T to C transition of the gene encoding glycoprotein IIIa leads to a common diallelic polymorphism Leu‐33→Pro (PLA1/A2). We studied the relationship between the PlA1/A2 polymorphism and platelet function in 80 healthy men, aged 20–25 years. Before aspirin ingestion, bleeding time (BT) was shorter in carriers of the PlA2 than in carriers of the PlA1/A1 allele. At 4 h after ingestion of 300 mg of aspirin, BT became prolonged, and the intergroup difference was enhanced. In seven out of 26 PLA2 allele carriers, aspirin shortened BT on average by 30 s, compared with only one among 54 subjects with the PlA1/A1 genotype. Thus, BT both at baseline and after aspirin depends on the PlA1/A2 polymorphism of glycoprotein IIIa. Carriers of the PlA2 allele appear to be more resistant to the antithrombotic action of aspirin.

Homocysteine and thrombosis: from basic science to clinical evidence

Homocysteine is a sulfhydryl-containing amino acid formed during the metabolism of methionine. Rapidly accumulating evidence links elevated homocysteine levels to thrombosis via several mechanisms such as increased tissue factor expression, attenuated anticoagulant processes, enhanced platelet reactivity, increased thrombin generation, augmented factor V activity, impaired fibrinolytic potential, and vascular injury, including endothelial dysfunction. Molecular mechanisms underlying prothrombotic actions of homocysteine are incompletely understood and involve oxidative stress, DNA hypomethylation, and proinflammatory effects. Current evidence from retrospective and prospective studies supports the concept that higher total plasma homocysteine concentration is associated with increased risk of coronary artery disease, stroke, and venous thromboembolism. Hyperhomocysteinemia is currently considered a relatively weak prothrombotic factor. It is still unclear whether administration of vitamins, that reduce homocysteine levels acting as cofactors of the enzymes involved in the methionine metabolism, may decrease the risk of arterial and/or venous thromboembolic events. Ongoing clinical trials might help clarify this issue.

Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease

Summary.  Background: Aspirin increases fibrin clot porosity and susceptibility to lysis. It is unknown whether other drugs, in combination with aspirin, used in the treatment of coronary artery disease (CAD) might affect clot structure and resistance to lysis. Aim: The aim of the study was to assess the effects of statins, fibrates, or angiotensin‐converting enzyme inhibitors (ACEIs) on fibrin clot properties. Patients and methods: In a randomized double‐blind study, men with advanced CAD taking low‐dose aspirin were assigned to receive one of the four drugs: simvastatin 40 mg day−1 (n = 13), atorvastatin 40 mg day−1 (n = 12), fenofibrate 160 mg day−1 (n = 12), and quinapril 10 mg day−1 (n = 11) for 28 ± 2 days. Moreover, CAD patients (n = 13) taking aspirin (75 mg day−1) for 8 weeks were studied after additional 4 weeks on an open‐label basis. Thirty men served as healthy controls. Plasma clot permeability and tissue plasminogen activator‐induced fibrinolysis were evaluated at baseline and after drug administration. Results: Permeability increased following the administration of simvastatin (by 20%; P = 0.01), atorvastatin (by 22%; P = 0.001), fenofibrate (by 16%; P = 0.02), and quinapril (by 13%; P = 0.04) like for aspirin (P < 0.001). Turbidity analysis showed that administration of any of the drugs was associated with higher maximum absorbancy, suggesting thicker fibers, and shorter fibrinolysis time (P < 0.001). Post‐treatment reduction in lysis time correlated with an increase in clot porosity in all the groups (r from 0.42 to 0.61; P from 0.01 to 0.001). Conclusions: Statins, fibrates, and ACEIs may increase plasma clot permeability and susceptibility to fibrinolysis in CAD patients receiving aspirin. This novel antithrombotic mechanism might contribute to clinical benefits of the drugs tested.